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Preparation method of Cefditoren Pivoxil

A technology of cefditoren pivoxil and its compounds, which is applied in the field of preparation of cefditoren pivoxil, can solve problems such as yield reduction, messy reaction, difficult purification process, etc., and achieve increased reactivity, mild reaction conditions, and product purity high effect

Active Publication Date: 2018-05-29
SHANDONG YUXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But in this method, become sodium salt reaction, need to react under strong alkali, the amide bond etc. in the product can be destroyed to a certain extent, then react with iodomethyl pivalate again, cause reaction messy, many by-products, Yield decreased, and due to by-products (such as Δ 3 isomer, E isomer, etc.) are similar to the product in nature and structure, the purification process is particularly difficult, and the sodium salt of cefditoren acid is not suitable for storage and has poor stability
In addition, there are few studies on the starting material 7-ATCA at present, and most of the existing technologies use 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE) as raw material to pass through phosphorus ylide and then combine with 4 -Methyl-5-thiazole carboxaldehyde undergoes Wittig reaction to obtain 7-ATCA
Although this method has simple reaction and easy operation, the Wittig reaction yield is not high, the reaction is slow (generally 20~24h) and the selectivity is poor, and the E-type isomer by-product is mixed in the Z-type product, due to its structure, Similar properties, difficult to separate, and may even remain in the final cefditoren pivoxil, affecting drug efficacy and safety

Method used

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  • Preparation method of Cefditoren Pivoxil
  • Preparation method of Cefditoren Pivoxil
  • Preparation method of Cefditoren Pivoxil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Step 1) Under nitrogen protection, 10.89g 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooct-2-ene-2carboxylic acid, 100mL acetonitrile, 46mmol N , put O-bistrimethylsilylacetamide (BSA) in the reaction bottle, stir the reaction at room temperature for 4h, add dropwise N,N-diethylaniline 4~6mL, trimethyl iodosilane (TMSI) 44mmol, in 10~ React at 15°C for 1 hour, add 11.02 g of triphenylphosphine, continue the reaction for 1 hour, add 7.34 g of sodium hexamethyldisilazide, stir at room temperature for 45 minutes, separate the organic layer and wash with water, then wash with 20% w / w NaCl aqueous solution, Anhydrous MgSO 4 After drying, 22.01 g of compound 4 was obtained, with a yield of 89%.

[0038] Step 2)

[0039] [C 4 MIm]PF 6 Preparation of ionic liquid: 6.896g KPF will be dissolved 6 50mL of acetone solution was placed in a 250mL three-necked flask, and then 10mL containing 5.47g [C 4 MIm]Br in acetone solution, a white precipitate appeared immediately, aft...

Embodiment 2

[0044] Step 1) Under nitrogen protection, 10.89g of 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooct-2-ene-2carboxylic acid, 100mL of acetonitrile, 40mmol N , put O-bistrimethylsilylacetamide (BSA) in the reaction bottle, stir the reaction at room temperature for 4h, add dropwise N,N-diethylaniline 4~6mL, trimethyl iodosilane (TMSI) 40mmol, in 10~ React at 15°C for 1 hour, add 10.49 g of triphenylphosphine, continue the reaction for 1 hour, add 7.34 g of sodium hexamethyldisilazide, stir at room temperature for 45 minutes, separate the organic layer and wash with water, then wash with 20% w / w NaCl aqueous solution, Anhydrous MgSO 4 After drying, 19.79 g of compound 4 was obtained, with a yield of 80%.

[0045] Step 2)

[0046] [C 4 MIm]PF 6 Preparation of ionic liquid: 6.896g KPF will be dissolved 6 50mL of acetone solution was placed in a 250mL three-necked flask, and then 10mL containing 5.47g [C 4 MIm]Br in acetone solution, a white precipitate appeared immediatel...

Embodiment 3

[0051] Step 1) Under nitrogen protection, 10.89g of 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooct-2-ene-2carboxylic acid, 100mL of acetonitrile, 52mmol N , put O-bistrimethylsilylacetamide (BSA) in the reaction bottle, stir the reaction at room temperature for 4h, add dropwise N,N-diethylaniline 4~6mL, trimethyl iodosilane (TMSI) 40mmol, in 10~ React at 15°C for 1 hour, add 11.54 g of triphenylphosphine, continue the reaction for 1 hour, add 7.34 g of sodium hexamethyldisilazide, stir at room temperature for 45 minutes, separate the organic layer and wash with water, then wash with 20% w / w NaCl aqueous solution, Anhydrous MgSO 4 After drying, 20.78 g of compound 4 was obtained, with a yield of 84%.

[0052] Step 2)

[0053] [C 4 MIm]PF 6 Preparation of ionic liquid: 6.896g KPF will be dissolved 6 50mL of acetone solution was placed in a 250mL three-necked flask, and then 10mL containing 5.47g [C 4 MIm]Br in acetone solution, a white precipitate appeared immediatel...

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Abstract

The invention relates to a preparation method of Cefditoren Pivoxil. The preparation method comprises steps as follows: 7-ACA (3-acetyloxymethyl-5-thio-7-amino-8-oxy-1-nitrogen heterobicyclic octyl-2-ene-2 carboxylic acid) is taken as a starting raw material and is subjected to iodination and Wittig reaction after silanization protection, and a Cefditoren parent nucleus 7-ATCA (7-amino-3-[(Z)-2-(4-methyl-5-thiazole) vinyl]-3-cephem-4-carboxylic acid) is generated; after amino protection of aminothiazole ethyl gallate, a compound 2 is produced from 7-ATCA under catalysis of AlMe3; the compound2 is subjected to an esterification reaction with iodomethyl pivalate under actions of a phase transfer catalyst and an acid adsorbent, the amino protection is removed, and a target product CefditorenPivoxil is obtained. According to the preparation method, reaction conditions are mild, product purity and yield are high, the process is stable, amplification is easy, and the method is applicable to industrial production.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a preparation method of cefditoren pivoxil. Background technique [0002] Cefditoren Pivoxil (Cefditoren Pivoxil), chemical name: 2,2-dimethylpropionyloxymethyl (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)- 2-Methoxyiminoacetamido]-3-[(Z)-2-(4-methyl-1,3-thiazol-5-yl)ethenyl]-8-oxo-5-thia- 1-Azabicyclo[4.2.0]oct-2-ene-2-carboxylate, a third-generation cephalosporin antibacterial drug, was developed by the Japanese Meiji Seika Company and was launched in Japan in 1994 under the trade name Meiact. This product is mainly used to treat infections caused by Gram-positive bacteria and Gram-negative bacteria, including infections caused by Streptococcus pneumoniae, Klebsiella pneumoniae, Staphylococcus aureus, Proteus, etc. the therapeutic effect. Its structural formula is as follows: [0003] [0004] Several preparation methods that have been reported about the synthesis of cefdito...

Claims

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Application Information

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IPC IPC(8): C07D501/24C07D501/04
CPCC07D501/04C07D501/24
Inventor 刘振腾陈雨张金宝王平
Owner SHANDONG YUXIN PHARMA CO LTD
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